A Phase II Study of R115777 (Zarnestra) (NSC # 702818, IND# 58,359) in Children With Recurrent or Progressive: High Grade Glioma, Medulloblastoma/PNET or Brainstem Glioma
A Phase II Study of R115777 (Zarnestra) (NSC # 702818, IND# 58,359) in Children With Recurrent or Progressive: High Grade Glioma, Medulloblastoma/PNET or Brainstem Glioma
This phase II trial is studying how well tipifarnib works in treating young patients with recurrent or progressive high-grade glioma, medulloblastoma, primitive neuroectodermal tumor, or brain stem glioma. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth.
OBJECTIVES:
I. Determine the response rate in pediatric patients with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor (PNET), or brain stem glioma treated with tipifarnib.
II. Determine the distribution of time to progression, time to treatment failure, and time to death in patients treated with this drug.
OUTLINE: This is an open-label, multicenter study. Patients are stratified according to disease (high-grade glioma vs recurrent or progressive medulloblastoma/primitive neuroectodermal tumor [PNET] vs progressive diffuse, intrinsic brain stem glioma).
Patients receive oral tipifarnib twice daily on days 1-21. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Inclusion Criteria:
Histologically confirmed brain tumor, including the following:
Progressive or relapsed disease after prior conventional therapy
Radiographic evidence of measurable disease
Performance status - Karnofsky 60-100% (over 16 years of age)
Performance status - Lansky 60-100% (16 years of age and under)
Performance status - ECOG 0-2
At least 8 weeks
Absolute neutrophil count at least 1,000/mm^3
Platelet count at least 100,000/mm^3 (transfusion independent)
Hemoglobin at least 8.0 g/dL (red blood cell transfusions allowed)
Bilirubin no greater than 1.5 times upper limit of normal (ULN)
SGPT and SGOT less than 2.5 times ULN
Creatinine clearance OR radioisotope glomerular filtration rate at least 70 mL/min
Maximum creatinine based on age as follows:
Shortening fraction at least 27% by echocardiogram
Ejection fraction at least 50% by MUGA
No dyspnea at rest
No exercise intolerance
Pulse oximetry greater than 94%*
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Seizure disorder is allowed provided it is well-controlled on non-enzyme-inducing anticonvulsants
No active graft-versus-host disease
No uncontrolled infection
No allergy to azoles (e.g., ketoconazole, itraconazole, or fluconazole)
Recovered from prior immunotherapy
At least 7 days since prior antineoplastic biologic agents
At least 1 month since prior autologous stem cell transplantation (SCT)
At least 6 months since prior allogeneic SCT
More than 1 week since prior growth factors
No concurrent immunomodulating agents
More than 2 weeks since prior myelosuppressive chemotherapy (4-6 weeks for nitrosoureas or temozolomide) and recovered
No concurrent anticancer chemotherapy
Concurrent dexamethasone allowed provided patient is on a stable or decreasing dose for at least 1 week prior to study entry
Concurrent corticosteroids allowed only for treatment of increased intracranial pressure
Recovered from prior radiotherapy
At least 2 weeks since prior local palliative radiotherapy (small port)
At least 3 months since prior craniospinal radiotherapy
At least 6 weeks since other prior substantial bone marrow radiotherapy
No concurrent palliative radiotherapy
No prior initiation of therapy on another phase II study
No concurrent participation in another therapeutic COG study
No concurrent enzyme-inducing anticonvulsants
No other concurrent anticancer or experimental drugs
No concurrent foods or medications that interfere with CYP3A4, including any of the following: